Compressed tablet formulation comprising non-steroidal anti-inflammatory drugs and methods

ABSTRACT

A compressed tablet composition comprising: a granular component comprising a plurality of solidified melt granules of a non-steroidal anti-inflammatory drug (NSAID) having a melting point in the range 30-300° C. and incorporating a disintegrant uniformly dispersed therein; characterised in that the granules comprise a continuous phase of said non-steroidal anti-inflammatory drug and further characterised in that the tablet composition comprises silicon dioxide present in an amount of 0.05-5.0% by weight of the composition. Preferably, the composition also contains an extra-granular component comprising the silicon dioxide and a lubricant. Further preferably the NSAID is ibuprofen which has a melting point in the range 75-77° C. Optionally the melting process can be carried out in an extruder. Tablets containing advantageous processing properties and dissolution characteristics are obtained.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a National Stage entry of International ApplicationNo. PCT/EP00/12193, filed Nov. 30, 2000, the entire specification claimsand drawings of which are incorporated herewith by reference.

This invention relates to compositions containing a non-steroidalanti-inflammatory drug, to processes to prepare them and to usesthereof.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used classof medicaments. They are a well defined group of compounds and includephenylpropionic acids such as ibuprofen, naproxen, ketoprofen andflurbiprofen. They are primarily used for the treatment of one or moreof pain, inflammation and fever, for example rheumatoid arthritis,ankylosing spondylitis, osteoarthritis, post-operative pain, post-partumpain and soft tissue injuries. One example is ibuprofen, which isavailable under prescription in the UK (eg Brufen (RTM)), generally atdoses up to 3200 mg per day. Ibuprofen is also available as anon-prescription drug in the UK (eg Nurofen (RTM)) primarily for thetreatment of symptoms of pain and fever including headache, migraine,rheumatic pain, muscular pain, backache, neuralgia, dysmenorrhoea,dental pain and colds and flu, generally at doses up to 1200 mg per day.

Ibuprofen and other NSAIDs are generally acidic and substantiallyinsoluble drugs. They are conveniently administered as an oralpharmaceutical composition in the form of tablets. Thus pharmaceuticallyacceptable excipients must be chosen for combination with the NSAID,with which the NSAID is compatible and with which it can form tabletshaving a satisfactory hardness and also release the medicament rapidlyinto the body so that it is available for absorption.

A major issue in connection with the disorders identified above is toimprove the onset of action of the NSAID, particularly in the treatmentof pain. It is believed that rapid disintegration of a formulationreleases the drug into the body quickly leading to a more rapid onset oftherapeutic action compared with a standard dosage form. Accordingly, itis desired to produce a solid dosage form for oral administrationadapted to disintegrate quickly in the gastro-intestinal tract. Many ofthe NSAIDs are acidic drugs, accordingly, absorption can be a problem inthe acidic conditions encountered in the stomach. Furthermore, althoughthe literature has proposed many formulations adapted to disintegratequickly, a major problem occurs with ibuprofen and other NSAIDs as theycan be administered in relatively high doses, eg up to 800 mg per unitdose. Thus, there is a problem to provide a dosage form which includesthe NSAID together with excipients useful to formulate the tablet intothe dosage form and also excipients useful to ensure rapiddisintegration, but not to provide a tablet that is too large forpatient consumption or cannot be produced according to standard largescale manufacturing processes. Furthermore, the solid dosage form mustbe sufficiently hard to withstand the rigours of the manufacturingprocess (for example as encountered during the stage of film coating ina perforated rotating drum and packaging etc) but must have appropriatedisintegration characteristics to ensure rapid release of the drug fromthe formulation and also appropriate dissolution characteristics.Another significant problem that must be overcome is to ensure that thecomposition is capable of being compressed without sticking to thepunches of the tabletting machine.

As an alternative to the general path of choosing particular excipientsand tabletting conditions or changing the form of the unit dose, oneavenue for investigation is to consider modifying the crystalline formof the NSAID in order to try to optimise its performance.

Earlier patent applications have considered heating ibuprofen, arelatively low melting drug, until molten and cooling to form agranulated composition, combining with optional tabletting excipientsand compressing into a tablet. Japanese Patent Kokai 81/120616 (1981)describes a process to prepare ibuprofen granules which allows theformation of smaller dosage forms, together with better flow propertiesof the granulate material prior to tabletting. In the illustrativeexamples of JP 81/120616, the ibuprofen is melted by heating andexcipients such as fine crystalline cellulose and calcium stearate areadded (optionally with hydroxypropyl starch) to form a dispersion of theinsoluble ingredients within the molten ibuprofen. The mixture is thencooled and crushed to form granules. The granules are either directlycompressed into tablets without the addition of further excipients ormixed with Aerosil (colloidal silicon dioxide) and filled into capsules.However, it was shown by measurements of blood concentration thatalthough smaller dosage forms and better flowability were achieved,there was no significant difference in the bioavailability betweentablets prepared as described in JPA 81/120616 and those of the artavailable before 1981.

European Patent Application 362728 (1990) relates to an easily flowableibuprofen granular composition that has improved storage and formulationproperties for direct tabletting. The molten ibuprofen is solidified ona contact cooling apparatus using a seeding process and is thencomminuted into a solid. The granulate formed consists wholly ofibuprofen. The process described requires the molten ibuprofen to berapidly congealed under specific conditions and then seeded when themolten ibuprofen solidifies, the resulting flakes being crushed underspecific milling conditions. The illustrative examples describe takinggranules formed by this process and combining them with a significantamount of necessary tabletting excipients such as microcrystallinecellulose, sodium starch glycolate, colloidal silicon dioxide andmagnesium stearate and compressing into tablets. In order to reduce thesize of the tablet it is desired to reduce the quantity ofextra-granular excipients necessary for combination with the ibuprofengranules prior to tabletting.

U.S. Pat. No. 5,240,712 (1993) discloses that molten ibuprofen may bepoured into capsules and gives examples of encapsulated dosage formscontaining ibuprofen, optionally containing excipients as a solidsolution or dispersion therein. The molten ibuprofen composition isfilled into a capsule and then allowed to solidify. The dosage formsthus produced need no further processing and can be directlyadministered to a patient. However, the capsules are of significant sizeand it is desired to produce a solid dosage form of relatively smallsize.

U.S. Pat. No. 5,667,807 (1997) also relates to heating ibuprofen untilmolten and producing tablets from the granular composition obtainedtherefrom. It contains illustrative examples of tablets produced firstlyby forming a mixture of ibuprofen with excipients (includingmicrocrystalline cellulose, maize starch, magnesium stearate andoptionally colloidal silicon dioxide and croscarmellose sodium), andthen heating and extruding said mixture in a melt extruder to produce anextrudate in which a part of the active is melted. It is said that thelow melting point active fulfils the function of a binder or of a solidsolvent. In a second part of the process, the cooled, comminutedgranules prepared from the extrudate are compressed into tablets afterthe optional inclusion of a lubricant. However, it is desired to reducethe number of excipients needing to be incorporated into the compositionand to improve the performance of the tablet.

WO 99/40943 discloses forming active agent/surfactant combinations usingselected processing conditions to at least partially place a eutectic ofthe active agent/surfactant combination into intimate contact withparticles of the active. The combinations are heated and subjected toforce, for example by processing in an extruder. However, the amount ofexcipient used contributes to increasing the size of the tabletsproduced therefrom.

Thus, in formulating a dosage form with granules produced by solidifyingmolten ibuprofen, it has previously been proposed that either (a) asignificant number of excipients are added to the molten ibuprofen andthe granules are taken for direct compression into tablets or (b)granules containing only ibuprofen are combined with a significantamount of additional tabletting excipients then compressed into tablets.

We have now found that if a disintegrating agent is incorporated into amolten NSAID and intimately combined therewith and then is cooled andmilled to produce a granule, a composition capable of tabletting withminimum tabletting excipients and having advantageous tabletting,disintegration and dissolution properties is provided, if silicondioxide is incorporated therein.

Accordingly, the present invention provides a compressed tabletcomposition comprising:

-   a granular component comprising a plurality of solidified melt    granules of a non-steroidal anti-inflammatory drug (NSAID) having a    melting point in the range 30-300° C. and incorporating a    disintegrant uniformly dispersed therein;-   characterised in that the granules comprise a continuous phase of    said non-steroidal anti-inflammatory drug and further characterised    in that the tablet composition comprises silicon dioxide present in    an amount of 0.05-5.0% by weight of the composition.

It has been found that formulations prepared according to the presentinvention have valuable disintegrating properties. Furthermore, thedissolution results show an unexpectedly high level of the NSAIDdissolved in the aqueous medium after relatively short periods of time.

A further advantage of the present invention lies in the small amount ofadditional tabletting excipients needed to prepare a dosage form, thusleading to advantages in processing and cost of the tablets and allowingsmaller dosage forms to be produced. Furthermore, the composition formedprior to tabletting has good flow properties and the resulting tabletshave a good hardness.

The surface area of the NSAID in the melt granule is significantlygreater than that of conventional crystals of the NSAID. In addition,the particle size is less than the particle size produced by micronisingNSAID particles which is a conventionally favoured method of improvingthe dissolution. It is surprising that the effect of the small amountsof silicon dioxide has the effect of causing the composition to disperseso quickly in aqueous conditions, especially in acidic conditions (suchas are found in the stomach) leading to a high percentage of NSAID beingdissolved within a relatively short period.

The invention allows the formulation of any relatively low melting NSAIDinto an acceptably tasting, readily disintegrating composition. Afavoured class of compounds are the 2-arylpropionic acids which aregenerally substantially insoluble and have poor taste properties. It isgenerally envisaged that the melting point of such compounds will be lowenough to allow the melting thereof using standard equipment. It is alsoimportant that there is not a deleterious effect on the ingredientsincorporated in the molten NSAID, for example the disintegrant. Thus,typical melting points of the low melting NSAIDs would be expected tofall within the range 30-300° C. Preferred NSAIDs have lower meltingpoints so that the melting process does not use significant amounts ofenergy, which thus has an effect on production costs. Preferred meltingpoints are in the range 30-200° C. (such as racemic naproxen, meltingpoint 156° C.), more preferably 30-150° C., further preferably 40-120°C. (such as racemic flurbiprofen, melting point 114° C.), mostpreferably 50-100° C. (such as racemic ibuprofen (melting point 75-77°C.), S(+)-ibuprofen (melting point 52-54° C.) and racemic ketoprofen(melting point 96° C.)). Preferred low-melting NSAIDs are naproxen,ketoprofen, flurbiprofen, ibuprofen or enantiomers (especially theS(+)-enantiomers) thereof. The invention is especially adapted for anibuprofen medicament. The term “ibuprofen medicament” includes racemicibuprofen and S(+)-ibuprofen which have low melting points and a verypoor after-taste in the mouth and throat. Most advantageous results areobtained with racemic ibuprofen which has a high dosage combined withpoor solubility properties.

The proportion of NSAID in the granular composition will depend on thedose desired for therapeutic effect. Low dose drugs, such asflurbiprofen and ketoprofen may form as little as 20% by weight (forexample 20-99%) of the composition in order to provide that the tabletis not too small. However, a preferred feature of the invention is thatlow-melting, high dose NSAIDs, such as ibuprofen, can be formulated intosmaller dosage forms. Accordingly, the NSAID will suitably form greaterthan 70% w/w of the granular component (for example 70-99% by weight),preferably 70-95%, further preferably 75-85% w/w of the granularcomponent. The NSAID will suitably form greater than 50% by weight ofthe tablet composition, for example 60-97% by weight, preferably 70-95%by weight, more preferably 70-90% by weight and most preferably 75-85%by weight of the composition.

The disintegrating agent has the effect of causing an NSAID tabletcomposition to disintegrate under the conditions found in thegastro-intestinal tract. Examples of disintegrating agents include oneor more of wheat starch, maize starch, potato starch, sodium starchglycolate, low-substituted hydroxypropyl cellulose, alginic acid,cross-linked polyvinylpyrrolidone, magnesium aluminium silicate andcroscarmellose sodium. Preferred disintegrating agents are those whichswell on the action of water thus causing the ingredients in the tabletto be pushed apart and out into the aqueous disintegration medium.Preferred disintegrating agents comprise one or more of croscarmellosesodium and sodium starch glycolate, especially croscarmellose sodium.The disintegrating agent is present at an effective disintegratingamount, for example up to 25% by weight of the composition, morepreferably 1-25% w/w, further preferably 3-20% w/w and most preferably8-17% by weight of the composition. The disintegrating agent willsuitably form 1-25% by weight of the granular component, preferably5-23% w/w and most preferably 8-20% by weight of the granular component.

Preferably the ratio of ibuprofen medicament to disintegrating agent inthe range is 30:1 to 1:1 parts by weight, preferably 20:1 to 2:1, morepreferably 10:1 to 3:1 parts by weight.

The silicon dioxide is insoluble and suitably has a surface area greaterthan 50 m²g⁻¹, more preferably greater than 100 m²g⁻¹, especially in therange 150-250 m²g⁻¹. Most preferably the silicon dioxide is colloidalsilicon dioxide (especially having a mean particle size less than 50 nmsuch as 5-40 nm), most preferably anhydrous colloidal silicon dioxide.The tapped density of the silicon dioxide is preferably in the range0.01-0.2 gcm⁻².

The silicon dioxide is incorporated in the composition to an extent of0.05-5.0% by weight (preferably 0.1-3% by weight, more preferably 0.2-1%by weight) of the composition. The silicon dioxide may be incorporatedin the granules. Preferably, if incorporated in the granules, it is usedto an extent of 0.1-1%, more preferably 0.2-0.8% by weight ofcomposition.

In the preparation of the granular component, the NSAID is melted. Underpressurised conditions, the drug may be melted at a temperature belowits normal melting point. Melting may be carried out according to knownmethods, including for example, heating in a vessel to a temperatureabove the melting point of the NSAID or by extrusion in a heatedextruder. The maximum temperature is determined by the stability of themolten drug and ingredients combined therewith. The drug may be heatedto any convenient temperature. Generally, the higher the temperature,the more quickly the drug will melt although this must be balanced bythe energy input required to heat the drug. For highest efficiency, itis generally envisaged that the NSAID will be heated to not more than25° C., preferably 5-10° C., above its melting point to keep energycosts to a minimum. Thus, a preferred heating range is 30-180° C., morepreferably 35-140° C. and further preferably 40-120° C. If the NSAID isextruded, generally the extruder is heated to a given temperature. Inaddition, the work on the NSAID by the screw configuration in theextruder will also contribute to melting the NSAID thereby reducing itsexternal applied temperature requirement. Accordingly the extruderbarrel may be heated to a temperature less than the melting point of theNSAID. For example, the normal melting point of racemic ibuprofen is75-77° C., however under conditions of force/pressure (such as may beencountered in an extruder or similar processing device), the externalapplied heat necessary to melt the ibuprofen may be reducedsignificantly through the mechanical heat generated by the intensemixing action within the extruder. It is generally envisaged that theextruder will be heated to a temperature not less than 25° C. below themelting point of the drug, preferably in the range from 15° C. below themelting point of the drug to 25° C. above the melting point of the drug,more preferably to a temperature in the range of 10° C. on each side ofthe melting point of the drug. Some extruders allow different zones tobe heated to different temperatures in the extruder. These temperaturescan be chosen as desired to ensure that the NSAID is fully melted.

When the NSAID is ibuprofen it may conveniently be heated in the range50-100° C., more preferably 60-100° C. When heated by conventionalheating means such as a water or steam bath it is preferably heated inthe range 75-90° C., more preferably 75-85° C. The ibuprofen may also beheated and subjected to conditions of force, such as by heat-extrudingthe ibuprofen, for example in a twin-screw extruder. The temperature ofthe ibuprofen in the extruder barrel is preferably in the range 66-96°C., preferably 70-82° C.

When the NSAID is substantially fully melted, a liquid is formed. TheNSAID should be fully melted so that on cooling, a single continuousphase of the NSAID is formed. The disintegrant is combined with themelted NSAID, either prior to melting or after the melting process. Thedisintegrant is most commonly insoluble in the ibuprofen melt and adispersion of the solid disintegrating agent within the liquid melt isproduced. The dispersion is mixed so that the disintegrating agent isuniformly or homogeneously combined with the melted NSAID. A uniformmixture is thus produced. The mixture is allowed to cool by methodshereinafter discussed until a solid is produced. As the mixture cools,it becomes more viscous. The NSAID which solidifies is then formed intomelt granules. Thus, as used herein, “solidified melt granules” meansgranules formed by combining the NSAID in fully molten form with adisintegrant and other optional tabletting excipients, cooling to atemperature below the melting point of the NSAID and forming the solidmass into granules. The granular composition comprises a plurality ofsuch granules.

The melt is allowed to solidify in any manner found convenient. Thisincludes both rapid cooling and slow cooling. For example, the moltenNSAID may be allowed to cool overnight at ordinary temperatures or in acooled vessel. The molten NSAID may be poured onto cooling trays whichmay be static or continuously moving. Static trays may be placed incooling cabinets. Moving trays or belts may have additional coolingmeans, such as cooled water. The cooled melt forms a solid and may bescraped off the belt or collected as it falls off one end of acontinuously moving belt.

The solidified melt incorporating the disintegrant may be formed intogranules by a plurality of methods. For example, it may be pulverisedinto granules. It may be milled and/or sieved. It may also be passedthrough a spray device such as a spray tower or spray granulator inwhich the molten material is sprayed from an orifice into a stream ofcooled air, allowed to congeal/solidify and then collected. If themolten NSAID is extruded, the extrudate may be cooled and then brokeninto conveniently sized pieces, followed by milling and or sieving.Alternatively, the extrudate may be extruded through holes and choppedinto suitably sized granules for tabletting.

The NSAID forms a continuous phase in the granule. That is to say thecrystalline structure of the NSAID is not interrupted by anothercrystalline structure. This may occur, for example, if the NSAID is onlypartially melted where the crystalline structure of the melted NSAID isinterrupted by the non-melted NSAID, thus providing that the NSAID doesnot have a single crystalline structure. The crystalline structure ofthe solidified melted NSAID is different from the crystalline structureof unmelted NSAID, for example in terms of particle size. Thus, incompositions according to the present invention, the NSAID is present ina single crystalline state and thus the NSAID continuous phase comprisesa single crystalline phase of the NSAID.

Although not necessary for the carrying out of the present invention, ifdesired the compressed tablet composition may comprise additionalexcipients.

For example, the composition may comprise a proportion of water-solubleor water-insoluble diluent. Suitable water-soluble diluent materialsinclude the sugar alcohols (such as xylitol, sorbitol, mannitol,erythritol), sugars (such as sucrose, fructose, lactose, dextrose),cyclodextrin, maltodextrin and salts of organic acids (eg sodium citrateand potassium citrate). Lactose, sodium citrate and potassium citrateare particularly preferred water-soluble diluents. Suitablewater-insoluble diluent materials include cellulose derivatives (such asmicrocrystalline cellulose) starch and derivatives thereof (such aspre-gelatinised starch), dicalcium phosphate, tricalcium phosphate,calcium sulphate, calcium carbonate. Microcrystalline cellulose anddicalcium phosphate are preferred water insoluble diluents. In a tabletadapted to disperse in water prior to administration, the level ofdiluent may be quite high, for example up to 50% (such as 0-50% w/w,preferably 0-40% w/w) by weight of the composition in order to achievethe desired dispersing properties. Preferably, in tablets for oraladministration, the diluent does not form greater than 25% by weight ofthe composition (eg 0-25% w/w), as it adds to the costs of thecomposition and to production costs. Thus, to minimise costs it may bepreferred that the diluent is added to the composition in an amount of0-20% by weight of the composition, more preferably 0-10% w/w. Ifpresent, it may be preferably used to an extent of 0.1-25% by weight ofthe composition, more preferably 0.1-20% w/w, further preferably 0.1-10%w/w and most preferably 1-5% by weight of the composition.

The diluent may preferably include a basic ingredient such as an alkalimetal salt for example an alkali metal carbonate, bicarbonate orcitrate, present to an extent of up to 50% by weight (eg in the range1-50% by weight), preferably up to 40% by weight (eg in the range 1-40%by weight) of the composition (more preferably 2-35% w/w and mostpreferably 10-20% w/w). Preferably, the alkali metal salt is sodium orpotassium. Further preferably, the salt is a citrate, carbonate orbicarbonate salt of sodium or potassium, more preferably sodiumbicarbonate or citrate. The ratio of NSAID (especially ibuprofenmedicament) to alkali metal salt may be in the range 100:1 to 1:1 partsby weight, preferably 5:1 to 1:1 parts by weight. Preferably, the alkalimetal salt is incorporated in any amount up to an equimolar amount withrespect to the NSAID (eg ibuprofen). Conveniently, a sub-molar amount ofalkali metal salt is incorporated. Thus the alkali metal compound mayform up to 100% w/w of the NSAID, preferably 50% w/w, more preferably upto 10% w/w, of the NSAID. In a preferred compressed tablet according tothe present invention, the NSAID (especially an ibuprofen medicament) isin admixture with the alkali metal salt. The alkali metal salt ispreferably incorporated into the extra-granular component for admixturewith the granular component prior to compression into a tablet.

The granular component may also include a surfactant, in an amountappropriate to the properties of the surfactant, preferably 0.05-10% byweight of the composition. Preferred surfactants are sodium laurylsulphate and poloxamer. They may be used to an extent of 0.05-8% byweight (preferably 0.1-5% by weight, more preferably 0.2-2% by weight)of the composition.

A preferred granular component comprises an NSAID (preferablyibuprofen), a disintegrant, a surfactant and optionally a diluent. Afurther preferred granular component consists essentially of an NSAID(preferably ibuprofen), a disintegrant and a surfactant. A furtherpreferred granular component consists essentially of an NSAID(preferably ibuprofen), a disintegrant, a surfactant and a diluent.

The melt granules in the granular composition preferably have a meanparticle size in the range 10-2000 μm, more preferably 50-1000 μm andmost preferably 100-400 μm. Valuable results are achieved when the bulkdensity of the melt granules is in the range 0.1-1 gml⁻¹, morepreferably 0.3-0.6 gml⁻¹. Further preferred properties are obtained whenthe tapped density is in the range 0.3-0.7 gml⁻¹ (more preferably0.4-0.6 gml⁻¹).

In a composition according to the present invention, it is preferredthat the granular component of melt granules is combined with anextra-granular component. Preferably the composition comprises agranular component in an amount of 60-99.95% (more preferably 70-99.9%by weight, especially 75-99.9% by weight, particularly 80-99.9% and mostpreferably 95-99.9% by weight) and 0.0540% extra-granular component(preferably 0.1-30%, especially 0.1-25%, particularly 0.1-20%, and mostpreferably 0.1-5%) by weight of the composition.

The extra-granular component comprises the ingredients incorporated inthe compressed tablet which are not contained in the solidified meltgranules. They may be mixed with the melt granules simultaneously or atsequential stages in the process to prepare the tablets. A particularadvantage of the present invention is preferably that all theingredients of the extra-granular component are combined with thegranular component at the same time and also that there does not have tobe significant processing of the ingredients in the extra-granularcomponent prior to combining with the granular compound. The compressedtablet comprises a uniform mixture of granular component andextra-granular component. The extra-granular component is suitablydistributed evenly throughout the composition.

A preferred compressed tablet composition of the present inventioncomprises:

-   a) 60-99% granular component by weight of the composition, said    granular component incorporating 0.005-1 parts by weight    disintegrant per part by weight of non-steroidal anti-inflammatory    drug; and-   b) 0.05-40% extra-granular component by weight of the composition.

Preferably, the silicon dioxide is present in the extra-granularcomponent. Further preferably, the silicon dioxide is present in theextra-granular component to an extent of 0.1-3%, more preferably 0.2-2%by weight of the composition.

Optionally a lubricant may be incorporated in the extra-granularcomponent for mixing with the granular component. Conventionallubricants for ibuprofen tablets may be used for example stearic acid,sodium lauryl sulphate, polyethylene glycol, hydrogenated vegetable oil,sodium stearyl fumarate, magnesium stearate or calcium stearate. Thesemay be present in an amount from 0.05-5% by weight, preferably 0.1-2% byweight of the composition. Anti-adherents such as talc, may further beincluded in an amount of up to 4% by weight of the dosage form, forexample 0.5-2% by weight of the dosage form, preferably as part of theextra-granular component.

An advantageous tablet composition according to the present inventioncomprises an extra-granular component comprising silicon dioxide and alubricant. This may form an intimate admixture with said granularcomponent prior to compression into a tablet. Preferably, theextra-granular component consists essentially of silicon dioxide and alubricant in a ratio of one part by weight silicon dioxide to 0.5-5parts by weight lubricant, more preferably 0.5-2 parts by weightlubricant.

Although not necessary for the production of compositions according tothe present invention, if desired, the dosage form may further comprisetabletting excipients such as a compressible diluent. This may becontained in the melt granule (as discussed above) or may be combinedwith the extra-granular ingredients prior to compression as part of theextra-granular component or may be incorporated as desired in bothcomponents. Examples of such compressible diluents include one or moreof a cellulose derivative (such as microcrystalline cellulose), starchand derivatives thereof (eg pre-gelatinised starch), soluble sugars (eglactose, fructose, dextrose, sucrose, dextrin), sugar alcohols (egxylitol, sorbitol, mannitol, erythritol), sodium chloride, dicalciumphosphate, tricalcium phosphate, calcium sulphate, mannitol, sorbitol,cyclodextrin, and maltodextrin and salts of organic acids (e.g. sodiumcitrate and potassium citrate). Microcrystalline cellulose and the saltsof organic acids are preferred as hereinabove discussed.

If necessary for tabletting a low dose drug, the diluent material mayform up to 80% by weight of the composition. Preferably, it is used toan extent of 0-30% by weight of the composition and more preferably0-20% of the total composition. If desired, the diluent may be added inan amount up to 30% by weight of the extra-granular component, althoughto minimise the size and cost of the dosage form, it is desired toinclude a minimum amount of such additional excipients. Accordingly, ifemployed, the diluent may suitably be included in the extra-granularcomponent in the range up to 20% by weight (ie 0.1-20%), preferably0.1-15%, more preferably 0.1-10%, desirably 1-5% by weight. As discussedhereinabove, the diluent may be present in the granular component, forexample 0-20% (such as 0.1-20%) by weight of the composition and/or inthe extra-granular component, for example 0-20% (such as 0.1-20%) byweight of the composition.

Other conventional tabletting excipients known to the person skilled inthe art may be incorporated in the compressed tablet compositionaccording to the present invention as desired, although it will beappreciated that a prime advantage of the present invention is that thenumber of excipients necessary to achieve a quickly disintegratingtablet with good dissolution characteristics is minimal.

A preferred compressed tablet composition comprises an intimate mixtureof:

-   a) a granular component comprising a solidified melt of an ibuprofen    medicament incorporating a disintegrant homogeneously dispersed    therein: and-   b) 0.05-5.0% silicon dioxide by weight of the composition.

In a further preferred compressed tablet composition according to thepresent invention, there is provided a compressed mixture of:

-   a) solidified melt granules comprising 70-97% ibuprofen by weight of    the granule (preferably 70-95% by weight), 3-25% croscarmellose    sodium by weight of the granule (preferably 5-20% by weight) and    0-20% diluent by weight of the granule (preferably 8-16% by weight)    uniformly dispersed therein, the ibuprofen being present in a    continuous phase;-   b) 0.05-5.0% w/w silicon dioxide; and optionally-   c) a lubricating agent.

In a further preferred composition according to the present inventionthere is provided, preferably as an intimate mixture,

-   a) 90-99.95% granular component by weight of the composition, said    granular component comprising solidified melt granules of ibuprofen    incorporating croscarmellose sodium and optionally a diluent    uniformly dispersed therein, said ibuprofen being present in a    single continuous phase and in an amount of 70-99% by weight of the    composition, said croscarmellose sodium being present in an amount    of 1-25% by weight of the composition and said diluent being present    in an amount of 0-20% by weight of the composition; and-   b) 0.05%-10% extra-granular component by weight of the composition    comprising:    -   i) 0.1-3% lubricant by weight of the composition; and    -   ii) 0.05-2% silicon dioxide by weight of the composition.

An advantageous compressed tablet composition according to the presentinvention comprises a uniform blend of:

-   a) a granular component comprising:    -   i) 70-90% ibuprofen by weight of the composition, said ibuprofen        being present as a continuous phase;    -   ii) 8-20% croscarmellose sodium by weight of the composition;    -   iii) 0-20% diluent by weight of the composition; and-   b) an extra-granular component comprising:    -   iv) 0.5%-2% stearic acid or a salt thereof by weight of the        composition;    -   v) 0.1-2.5% silicon dioxide by weight of the composition the sum        of components (i) to (v) being greater than 99% by weight of the        composition.

Most preferably, the granular component consists essentially (ie greaterthan 98% by weight of the composition) of ibuprofen, croscarmellosesodium and a diluent (preferably a salt (eg an alkali metal salt) of anorganic acid or microcrystalline cellulose). In a further advantageouscomposition, the granular component consists essentially of ibuprofen,croscarmellose sodium and a surfactant. Particular advantages are alsoachieved if the granular component consists essentially of ibuprofen,croscarmellose sodium, a diluent (preferably microcrystalline celluloseor an alkali metal salt of an organic acid) and a surfactant (preferablysodium lauryl sulphate or a poloxamer). For example, an advantageouscomposition may consist essentially of (ie greater than 98% by weight ofthe composition) a uniform mixture of 75-95% ibuprofen by weight of thegranular composition, 5-20% disintegrant by weight of the granularcomposition and 0-20% diluent by weight of the granular composition, thecomposition comprising solidified melt granules of ibuprofen and theibuprofen being present as a single continuous phase.

The compressed tablet composition of the present invention may, ifdesired, include other compatible pharmacologically active ingredientsand/or enhancing agents. Thus, for example, the dosage form may includeany other ingredient commonly used in a composition useful to treatpain, inflammation and/or fever, for example caffeine or anotherxanthine derivative, another analgesic, for example codeine, a skeletalmuscle relaxant: an antihistamine (e.g. acrivastine, astemizole,azatadine, azelastine, bromodiphenhydramine, brompheniramine,carbinoxamine, cetirizine, chlorpheniramine, cyproheptadine,dexbromopheniramine, dexchloropheniramine, diphenhydramine, ebastine,ketotifen, lodoxamide, loratidine, levocabastine, mequitazine,oxatomide, phenindamine, phenyltoloxamine, pyrilamine, setastine,tazifylline, temelastine, terfenidine, tripelennamine or triprolidine(preferably non-sedating antihistamines are employed)); a decongestant(eg pseudoephedrine, phenylpropanolamine and phenylephrine); a coughsuppressant (eg caramiphen, codeine or dextromethorpan); and/or anexpectorant (eg guaifenesin, potassium citrate, potassiumguaiacolsuphonate, potassium sulphate and terpin hydrate).

Such extra active ingredients and/or enhancing agents may beincorporated in the melt granules or in the extra-granular componentwhich is combined with the melt granule prior to formulation into acompressed tablet.

The present invention also provides a composition comprising a granularcomponent consisting essentially of a uniform mixture of a low meltingNSAID (especially an ibuprofen medicament) and croscarmellose sodium inthe form of solidified melt granules.

In a further aspect of the present invention, there is provided agranulate comprising a plurality of solidified melt granules, said,granules comprising a continuous phase of ibuprofen and consistingessentially of a uniform mixture of 70-95% ibuprofen by weight of thegranule, 5-20% disintegrant by weight of the granule and 0-20% diluentby weight of the granule. A preferred feature of the granule is thefurther inclusion of a surfactant.

Ibuprofen and its derivatives are primarily anti-inflammatory, analgesicand anti-pyretic agents but have also been proposed for othertherapeutic uses, including the treatment of periodontal bone loss,pruritus and Alzheimer's disease. The dosage forms of the presentinvention are therefore indicated for use in the treatment of alltherapeutic uses for which ibuprofen is effective, including rheumatoidarthritis, osteoarthritis, ankylosing spondylitis, seronegativearthropathies, periarticular disorders and soft tissue injuries. Theymay also be used in the treatment of postoperative pain, postpartumpain, dental pain, dysmenorrhoea, headache, migraine, rheumatic pain,muscular pain, backache, neuralgia and/or musculoskeletal pain or thepain or discomfort associated with the following: respiratoryinfections, colds or influenza, gout or morning stiffness.

Accordingly, in another aspect of the present invention there isprovided a composition according to the present invention for use in thetreatment of pain and/or inflammation and/or fever. Furthermore, theinvention also provides a method of treating pain and/or inflammationand/or fever comprising the administration of a composition according tothe present invention to a mammal in need thereof.

Unit dosages for effective therapy are known to those skilled in the artfor each NSAID. For example, they may comprise the NSAID to an extent of5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 500 mg, 600 mg and 800 mg. Where derivatives areemployed, normally the precise unit dosages are chosen to give theequivalent NSAID doses given above. For the treatments described hereinthe maximum daily dose of ibuprofen is generally 3200 mg. A single unitdaily dose may be 100 mg. Preferred unit doses are in the range 100-400mg, more preferably 100-300 mg and especially 200 mg ibuprofen. Themaximum daily dose of flurbiprofen is generally 300 mg. A single unitdose may be 12.5 mg. Preferred unit doses are in the range 12.5-150 mg,more preferably 25-100 mg and especially 50 mg flurbiprofen. The maximumdaily dose of naproxen is generally 1500 mg. A single unit daily dosemay be 125 mg. Preferred unit doses are in the range 220-750 mg, morepreferably 220-500 mg and especially 220-250 mg naproxen. The maximumdaily dose of ketoprofen is generally 200 mg. A single unit dose may be25 mg. Preferred unit doses are in the range 25-100 mg, more preferably25-75 mg and especially 50 mg ketoprofen.

The compressed tablet composition preferably comprises a combination ofthe granular component with an extra-granular component comprisingsilicon dioxide and optionally a lubricant. This combination may takethe form of a uniform or homogeneous blend capable of being mixed withother ingredients as desired and compressed into tablets. The tabletcomposition may be swallowed or dispersed in water prior to ingestion.Preferably the tablet composition releases the ibuprofen medicament inthe stomach or gastro-intestinal tract.

In a further aspect, the present invention provides use of silicondioxide in an extra-granular component combined with a granularcomponent in a compressed composition, said granular componentcomprising a plurality of solidified melt granules of a low melting(e.g. melting point is in the range 30-300° C.) non-steroidalanti-inflammatory drug incorporating a disintegrant and optionally adiluent homogeneously dispersed therethrough, the composition comprising0.05-5% silicon dioxide by weight of the composition and the granulescomprising a continuous phase of said non-steroidal anti-inflammatorydrug.

In yet a further aspect, the present invention provides a process toprepare a compressed tablet composition comprising a non-steroidalanti-inflammatory drug having a melting point in the range 30-300° C.characterised by:

-   a) combining said drug in fully molten form with a disintegrant to    form a uniform mixture;-   b) cooling said mixture to form a solidified melt;-   c) forming said solidified melt into granules;-   d) compressing said granules, optionally with an extra-granular    excipient, to form a tablet.

The disintegrating agent may be sole ingredient incorporated within theNSAID (preferably ibuprofen) melt granules or it may be combined with adiluent and optionally a surfactant and other tabletting excipients.Accordingly, the granular composition may consist essentially of (iegreater than 98% by weight of the composition) an ibuprofen medicamentand disintegrating agent or it may consist of an ibuprofen medicament, adisintegrant, a diluent and optionally a surfactant. Thus the diluentand optional surfactant may be combined with the disintegrant and thedrug in fully molten form. A tablet composition according to the presentinvention may be prepared by incorporating silicon dioxide andoptionally and other excipients within the composition to be tabletted,preferably to form a powder blend, followed by compression into tablets.

The abovementioned process may be carried out in a number of ways. Inone method, the NSAID is heated in a suitable vessel until molten. Thedisintegrating agent may then be added to the molten mass and thoroughlycombined therewith to form a homogeneous mixture. Optional extraexcipients may also be blended into the molten NSAID simultaneously orsequentially. The molten mixture may then be discharged into anappropriate cooling system, for example a cooled belt which maycontinuously rotate and deliver the cooled melt to a comminuting devicesuch as a scraper bar and/or a mill.

In a further process, the non-steroidal anti-inflammatory drug may becombined with the disintegrant and optional tabletting excipients, eg adiluent, and then heated together until said non-steroidalanti-inflammatory drug is fully molten. In yet a further process theNSAID and disintegrant are combined and heated together until said NSAIDis fully molten and any further desired tabletting excipients uniformlyblended with the mixture.

In another method, the NSAID and disintegrating agent are fed into anextruder type system (preferably having first been combined by blendingtogether). The materials are heated and mixed in the extruder until theNSAID is fully molten and a uniform mixture is produced. The NSAID anddisintegrant are extruded and the extrudate cooled. Preferably, theNSAID and the disintegrant are extruded in a twin screw extruder. Thehot mass (comprising the NSAID and disintegrant) extruded forms anagglomerated mass which may be collected and, if desired, milled to formgranules.

In a further method, after heating or heat-extrusion the NSAID anddisintegrating agent may be cooled by feeding to a spray tower dryer inwhich the molten mass is sprayed into the path of a stream of cold airand the dried solid mass collected.

The granular component may be tabletted directly in the absence ofextra-granular component or it may be combined with an extra-granularcomponent and fed to a tabletting machine to be compressed into tablets.Preferably the extra-granular component comprises silicon dioxide andoptionally a lubricant. Further preferably, the extra-granular componentcomprises silicon dioxide and a lubricant.

In a preferred aspect of the present invention, there is provided aprocess to prepare an ibuprofen granular composition comprising meltingan ibuprofen medicament (preferably ibuprofen), incorporating adisintegrating agent uniformly within the melted ibuprofen medicament,allowing said ibuprofen medicament to cool to form a solid andcomminuting said melt to form a granular composition. The disintegratingagent is thus generally combined with the ibuprofen medicament to form auniform mixture of solid disintegrating agent in the liquid ibuprofenmedicament melt prior to cooling.

The compressed tablet composition of the present invention mayoptionally be coated with a film coat, for example based on aconventional cellulose polymer such as hydroxypropylmethylcellulose, ora conventional sugar coat, for example based on sucrose or lactose.

The granular composition, may if desired be combined with a flow acidsuch as silicon dioxide and filled into capsules. Advantageousdissolution results can be obtained. This does not fall within the scopeof the present invention.

The invention is illustrated by the following non-limiting Examples. Inthe Examples, the racemic ibuprofen and racemic flurbiprofen isavailable from Knoll Pharma, Nottingham, GB; colloidal silicon dioxide(also known as colloidal silica) is available from Degussa, Frankfurt,DE under the trade name Aerosil 200; Croscarmellose sodium is availablefrom the FMC Corporation, Brussels, BE under the tradename Ac-Di-Sol;and sodium starch glycolate is available from Edward Mendell, Reigate,GB under the tradename Explotab; Poloxamer is available from BASF, DEunder the trade name Pluronic F68; Dicalcium phosphate is availableunder the trade name Emcompress; Hydrogenated Castor oil is availablefrom BASF, DE under the trade name Cremophor RH40, Microcrystallinecellulose is available from the FMC Corporation, Brussels, BE under thetrade name Avicel PH 101.

Dissolution Measurement

The dissolution was measured using the dissolution method described inthe US Pharmacopoeia Vol. 23, page 1791, Apparatus 2 using paddles at 50rpm and a phosphate buffer (selected at pH 7.2 and/or pH 6.0 and/or pH5.8).

Friability Measurement

This test for the robustness of the tablet is a standard friabilitytest, namely the rotation of 20 tablets for a given time period at 25rpm in a friabulator (TAR 20 manufactured by ERWEKA). The followingmeasurements were made:

-   1. The number of capped or broken tablets;-   2. The % weight loss from the tablet.    Crushing Strength (N)

The crushing strength is a measure of the hardness of a tablet. It wasmeasured by recording the diametrical crushing strength when the tabletwas broken between the motorised jaws of a Schleuniger crushing strengthtester. The range of crushing strengths of five tablets prepared witheach Example formulation is given.

Disintegration Time (Minutes)

The disintegration time can be measured using the disintegration methoddescribed in the European Pharmacopoeia 1986, Ref V.5.1.1 (updated 1995)using tap water (pH approximately 7) as the liquid. The method providesthe time by which six tablets prepared with each Example formulationdisintegrates.

Granulation Apparatus

The spray granulator was the PFB 28 available from APV, Denmark. Thespray tower was FBSD 66 available from APV, Denmark. The twin screwextruders were the MP19 (19 mm barrel) and MP40 PC (40 mm barrel)available from APV, UK.

EXAMPLE 1

(% w/w) Granular Component: Ibuprofen 93.9 Croscarmellose Sodium 4.7Extra-granular Component: Colloidal Silica 0.5 Stearic Acid 0.9

EXAMPLE 1(a) Preparation of Granular Component

In the illustrative process, the ibuprofen was first melted by heatingto approximately 75° C. in a stainless steel vessel until fully molten.The disintegrating agent (croscarmellose sodium) was then added to themolten ibuprofen and mixed for 5-10 minutes until uniformly dispersed.The molten mixture was poured onto a stainless steel tray and cooledover a period of up to 60 minutes, ensuring that the suspension wasmaintained. The mass thus formed was milled by passing through a conemill having a screen with a round hole size of 1 mm. The resultinggranules were collected.

EXAMPLE 1(b) Preparation of Tablets

The basing ingredients, namely silicon dioxide and stearic acid (alubricant) were blended simultaneously with the granular composition forapproximately 15 minutes in a blender. The blended material was fed to atabletting machine and compressed into tablets containing 200 mgibuprofen.

EXAMPLES 2-4

Ex 2 Ex 3 Ex 4 (% w/w) (% w/w) (% w/w) Ibuprofen 91.3 89.7 85.8Croscarmellose Sodium 7.3 9.0 12.9 Colloidal Silica 0.5 0.4 0.4 StearicAcid 0.9 0.9 0.9

Examples 2-4 were prepared in the same manner as described in Example 1to produce tablets containing 200 mg ibuprofen.

EXAMPLES 5-8

Ex 5 Ex 6 Ex 7 Ex 8 (% w/w) (% w/w) (% w/w) (% w/w) Ibuprofen 93.9 91.389.7 85.8 Sodium Starch Glycolate 4.7 7.3 9.0 12.9 Colloidal Silica 0.50.5 0.4 0.4 Stearic Acid 0.9 0.9 0.9 0.9

Examples 5-8 were prepared in the same manner as described in Example 1except that sodium starch glycolate was used as the disintegratingagent. Tablets containing 200 mg ibuprofen were prepared.

EXAMPLES 9-12

Ex 9 Ex 10 Ex 11 Ex 12 (% w/w) (% w/w) (% w/w) (% w/w) GranularComponent: Ibuprofen 66.2 73.9 63.3 86.6 Croscarmellose Sodium 5.3 5.95.1 6.9 Extra-granular component: Colloidal Silica 1.0 1.1 0.6 1.3Stearic Acid 0.7 0.7 0.9 0.9 Sodium carbonate — 18.4 — — SodiumBicarbonate 26.8 — — — Sodium citrate — — 30.1 4.3

Examples 9-12 were prepared in the same manner as described in Example1, except that a basic excipient (sodium citrate/sodium carbonate/sodiumbicarbonate) was included in the extra-granular component forcombination with the granular component. Tablets or component containing200 mg ibuprofen were prepared. The dissolution results of tabletsbefore storage are given in Table 1 below. Table 2 gives the dissolutionresults for Examples 2 and 4 after storage for 3 months at 40° C. and75% relative humidity and shows that a good performance is maintainedeven on storage. Table 3 relates to the dissolution performance ofExample 9 at different pH's. It shows that valuable dissolutionproperties are obtained even when the pH of the dissolution medium islowered.

TABLE 1 Dissolution Results at pH 7.2 of Example 1-9 tablets beforestorage Dissolution Time: Example: 10 mins 20 mins 30 mins 45 mins 60mins 1 >100% >100% >100% >100% >100% 2  98.2% >100% >100% >100% >100% 3 88.5% >100% >100% >100% >100% 4  84.6%  94.4%  95.9%  96.0%  96.2% 5 87.3% >100% >100% >100% >100% 6 >100% >100% >100% >100% >100% 7  75.0% 98.4% >100% >100% >100% 8  88.2% >100% >100% >100% >100% 9  89.2% 98.4%  98.4%  98.8%  98.5%

TABLE 2 Dissolution Results at pH 7.2 on Storage of Examples 2 and 4 for3 months at 40° C./75% Relative Humidity Dissolution Time: Example: 10mins 20 mins 30 mins 45 mins 60 mins 2 83.9% 97.9% 99.4% 99.6% 99.3% 484.5% 91.3% 90.5% 92.3% 92.3%

TABLE 3 Example 9: Dissolution Results: pH 7.2 and 5.8 Dissolution Time:10 mins 20 mins 30 mins 45 mins 60 mins pH 7.2 89.2% 98.4% 98.4% 98.8%98.5% pH 5.8 46.3% 61.6% 69.9% 77.5% 83.8%

It is noted that although at the lower pH a smaller percentage ofibuprofen is dissolved, this reflects the problems associated with thesolubility of ibuprofen in an acidic medium. The valuable properties ofthe present formulation are shown in that over 60% of the ibuprofen hasdissolved in 20 minutes, even at pH 5.8.

EXAMPLES 13-17

Ex 13 Ex 14 Ex 15 Ex 16 Ex 17 (% (% (% (% (% w/w) w/w) w/w) w/w) w/w)Ibuprofen 85.7 85.4 85.1 84.7 84.4 Croscarmellose Sodium 12.9 12.8 12.812.7 12.7 Colloidal Silica 0.5 0.9 1.2 1.7 2.1 Stearic Acid 0.9 0.9 0.90.9 0.8

Examples 13-17 were prepared in the same manner as described in Example1 to produce tablets containing 200 mg ibuprofen. The dissolutionresults are given Tables 4 (pH 7.2) and 5 (pH 5.8) below.

TABLE 4 Dissolution Results at pH 7.2 Time (min) Ex 13 Ex 14 Ex 15 Ex 16Ex 17 0 0.0% 0.0% 0.0% 0.0%   0.0% 5 77.1% 66.3% 69.6% 73.2%  89.4% 1087.3% 82.0% 85.9% 86.6%  98.1% 20 96.8% 98.4% 99.1% 98.6% >100% 30 98.2%99.6% 99.6% 99.3% >100% 45 98.3% 99.6% 99.6% 99.4% >100% 60 98.3% 99.7%99.6% 99.4% >100%

TABLE 5 Dissolution Results at pH 5.8 Time (min) Ex 13 Ex 14 Ex 15 Ex 16Ex 17 0 0.0% 0.0% 0.0% 0.0% 0.0% 5 30.4% 28.5% 24.1% 29.1% 35.3% 1051.2% 47.0% 43.0% 48.0% 56.3% 20 69.9% 64.3% 63.7% 66.0% 71.4% 30 77.6%72.8% 75.8% 79.0% 75.9% 45 83.7% 85.0% 90.3% 91.3% 78.4% 60 88.0% 93.2%95.5% 96.3% 80.0%

EXAMPLES 8-21

Ex 18 Ex 19 Ex 20 Ex 21 (% w/w) (% w/w) (% w/w) (% w/w) Granularcomponent: Ibuprofen 79.0 84.1 84.0 85.7 Croscarmellose Sodium 11.9 12.612.6 12.9 Poloxamer 7.9 2.1 — — Sodium Lauryl Sulphate — — 2.2 0.2Extra-granular component: Colloidal Silica 0.4 0.4 0.4 0.4 Stearic Acid0.8 0.8 0.8 0.8

Examples 18-21 were prepared in the same manner as described in Example1, except that a surfactant (Poloxamer/sodium lauryl sulphate) wasdispersed within the molten ibuprofen after the croscarmellose sodiumhad been dispersed uniformly within the molten ibuprofen. Tabletscontaining 200 mg ibuprofen were prepared.

The dissolution results for the tablets of Examples 18 to 21 at pH 7.2and 5.8 are given in Table 6 (a) and (b) below.

TABLE 6(a) Dissolution Results Example 18 Example 19 Time (min) pH 7.2pH 5.8 pH 7.2 pH 5.8 0  0.0%   0.0%  0.0%   0.0% 5 38.5%  24.0% 44.6% 26.0% 10 79.2%  59.1% 95.5%  73.7% 20 96.2%  91.3% 99.5%  95.2% 3096.4%  98.0% 99.6% >100% 45 96.4% >100% 99.6% >100% 60 96.4% >100% 99.6%>100%

TABLE 6(b) Dissolution Results Example 20 Example 21 Time (min) pH 7.2pH 5.8 pH 7.2 pH 5.8 0  0.0%  0.0%  0.0%  0.0% 5 31.9% 19.1% 90.1% 54.8%10 73.7% 57.8% 96.6% 76.9% 20 95.9% 90.4% 97.0% 89.8% 30 97.4% 96.6%97.2% 94.0% 45 97.5% 98.1% 97.3% 96.3% 60 97.5% 98.1% 97.3% 97.2%

EXAMPLES 22-26

Ex22 Ex 23 Ex 24 Ex 25 Ex 26 (% w/w) (% w/w) (% w/w) (% w/w) (% w/w)Granular Composition: Ibuprofen 82.4  82.4  79.0  82.4  70.6 Croscarmellose sodium 12.3  12.3  11.9  12.3  10.6  Extra-granularComponent: Microcrystalline cellulose 4.1 — — — 17.6  Lactose — 4.1 7.9— — Dicalcium phosphate — — — 4.1 — Colloidal silicon dioxide 0.4 0.40.4 0.4 0.4 Stearic acid 0.8 0.8 0.8 0.8 0.8

Examples 22-26 were prepared in the same manner as described in Example1, except that a diluent (microcrystalline cellulose/lactose/dicalciumphosphate) was included in the extra-granular component. Tabletscontaining 200 mg ibuprofen were prepared.

The dissolution results for each Example at pH 7.2 are given in Table 7below.

TABLE 7 Dissolution Results at pH 7.2 Time (min) Ex 22 Ex 23 Ex 24 Ex 25Ex 26 0  0.0% 0.0% 0.0% 0.0%   0.0% 5  78.8% 71.5% 85.2% 79.0%  84.1% 10 87.7% 82.9% 94.3% 87.3%  95.6% 20  95.4% 91.2% 98.2% 93.9% >100% 30100.0% 94.6% 98.6% 96.6% >100% 45  >100% 95.1% 98.7% 96.7% >100% 60 >100% 95.1% 98.7% 96.7% >100%

EXAMPLES 27-28

Ex 27 Ex 28 (% w/w) (% w/w) Granular Component: Ibuprofen 79.0 70.6Croscarmellose sodium 11.9 10.6 Microcrystalline cellulose 7.9 —Dicalcium phosphate — 17.6 Extra-granular component: Colloidal silicondioxide 0.4 0.4 Stearic acid 0.8 0.8

Examples 27 and 28 were prepared in the same manner as described inExample 1, except that a diluent (microcrystalline cellulose/dicalciumphosphate) was dispersed within the molten ibuprofen after thecroscarmellose sodium had been dispersed uniformly within the moltenibuprofen. Tablets containing 200 mg ibuprofen were prepared. Thedissolution results at pH 7.2 are given in Table 8 below

EXAMPLES 29-30

Ex 29 Ex 30 (% w/w) (% w/w) Granular Component: Ibuprofen 70.6 79.1Croscarmellose sodium 10.6 11.9 Lactose 8.8 — Dicalcium phosphate — 3.9Extra-granular component: Colloidal silicon dioxide 0.4 0.4 Stearic acid0.8 0.8 Lactose 8.8 — Dicalcium phosphate — 3.9

Examples 29 and 30 were prepared in the same manner as described inExample 1, except that a half portion of a diluent (lactose/dicalciumphosphate) was dispersed within the molten ibuprofen after thedisintegrant had been uniformly dispersed within the molten ibuprofenand the remaining half portion of diluent was included in theextra-granular component. Tablets containing 200 mg ibuprofen wereprepared. The dissolution results for each Example at pH 7.2 are givenin Table 8 below.

TABLE 8 Dissolution Results at pH 7.2 Time (min) Ex 27 Ex 28 Ex 29 Ex 300  0.0%  0.0%  0.0%  0.0% 5 87.7% 50.6% 82.5% 82.8% 10 95.3% 59.5% 93.0%90.1% 20 98.4% 67.0% 95.8% 92.3% 30 98.8% 71.3% 95.7% 93.0% 45 98.9%75.6% 95.7% 93.7% 60 98.9% 78.8% 95.7% 94.1%

EXAMPLE 31

Ex 31 (% w/w) Flurbiprofen 21.7 Croscarmellose sodium 3.3 Colloidalsilicon dioxide 0.1 Stearic acid 0.2 Microcrystalline cellulose 74.7

Example 31 was prepared in the same manner as described in Example 1except that flurbiprofen was used as the NSAID and microcrystallinecellulose was included in the extra-granular component i.e. withcolloidal silicon dioxide and stearic acid. Tablets containing 50 mgflurbiprofen were prepared. The dissolution results at pH 7.2 are givenin Table 9 below.

TABLE 9 Dissolution Results at pH 7.2 Time (min) Ex 31 0  0.0% 5 82.8%10 85.6% 20 86.0% 30 86.1% 45 86.2% 60 86.3%

EXAMPLES 32-34

Ex 32 Ex 33 Ex 34 (% w/w) (% w/w) (% w/w) Ibuprofen 82.3 79.0 76.0Croscarmellose sodium 16.5 19.8 22.8 Colloidal silicon dioxide 0.4 0.40.4 Stearic acid 0.8 0.8 0.8

Examples 32-34 were prepared in the same way as described in Example 1to provide tablets containing 200 mg ibuprofen. The dissolution resultsare given in Tables 10 (pH 7.2) and 11 (pH 5.8) below.

TABLE 10 Dissolution Results at pH 7.2 Time (min) Ex 32 Ex 33 Ex 34 0 0.0%  0.0%  0.0% 5 58.0% 70.9% 39.7% 10 76.9% 82.2% 60.9% 20 89.6%92.3% 80.8% 30 96.8% 95.9% 90.9% 45 98.5% 97.2% 97.1% 60 98.6% 97.2%97.3%

TABLE 11 Dissolution Results at pH 5.8 Time (min) Ex 32 Ex 33 Ex 34 0 0.0%  0.0%  0.0% 5 34.7% 37.9% 23.1% 10 62.1% 68.7% 47.3% 20 87.1%90.6% 70.8% 30 95.7% 97.3% 85.7% 45 99.0% 99.2% 93.1% 60 99.7% 99.0%94.3%

EXAMPLES 35-38

Ex 35 Ex 36 Ex 37 Ex 38 (% w/w) (% w/w) (% w/w) (% w/w) GranularComponent: Ibuprofen 85.6 85.1 84.8 84.4 Croscarmellose sodium 12.8 12.812.8 12.8 Colloidal silicon dioxide 0.8 1.3 1.6 2.0 Extra-granularcomponent: Stearic acid 0.8 0.8 0.8 0.8

Examples 35-38 were prepared in the same way as described in Example 1except that the colloidal silicon dioxide was dispersed uniformly withinthe molten ibuprofen before the disintegrant was uniformly dispersedwithin the molten ibuprofen. Tablets containing 200 mg ibuprofen wereproduced. The dissolution results are given in Table 12 below.

TABLE 12 Dissolution Results at pH 7.2 Time (min) Ex 35 Ex 36 Ex 37 Ex38 0  0.0%  0.0%  0.0%  0.0% 5 72.7% 64.8% 72.7% 78.1% 10 85.0% 75.8%90.1% 89.4% 20 92.8% 84.5% 96.1% 95.2% 30 97.8% 95.2% 97.4% 98.1% 4598.3% 99.0% 98.4% 98.2% 60 98.5% 99.5% 98.4% 98.2%

EXAMPLES 39-42

Ex 39 Ex 40 Ex 41 Ex 42 (% w/w) (% w/w) (% w/w) (% w/w) Granularcomponent: Ibuprofen 85.82 85.6 85.5 82.3 Croscarmellose Sodium 12.8612.9 12.8 12.3 Sodium lauryl sulphate 0.04 0.2 0.4 4.1 Extra-granularcomponent: Colloidal Silica 0.43 0.4 0.4 0.4 Stearic Acid 0.85 0.9 0.90.9

Examples 39-42 were prepared in the same way as described in Example 1except that sodium lauryl sulphate was dispersed uniformly within themolten ibuprofen after the disintegrant had been uniformly dispersedwithin the ibuprofen melt. Tablets containing 200 mg ibuprofen wereproduced. The dissolution results are given in Table 13 below.

TABLE 13 Dissolution Results at pH 7.2 Time (min) Ex 39 Ex 40 Ex 41 Ex42 0   0.0%  0.0%  0.0%   0.0% 5  95.7% 76.0% 62.7%  24.0% 10 >100%95.9% 81.8%  50.0% 20 >100% 98.7% 97.3%  74.4% 30 >100% 98.8% 99.2% 89.4% 45 >100% 98.8% 99.2% >100% 60 >100% 98.8% 99.2% >100%

EXAMPLE 43

(% w/w) Granular Component: Ibuprofen 82.6 Croscarmellose sodium 12.4Hydrogenated Castor Oil 2.1 Extra-granular component: Colloidal silicondioxide 2.1 Stearic acid 0.8

Example 43 was prepared in the same way as described in Example 1 exceptthat hydrogenated castor oil was dispersed uniformly within the moltenibuprofen after the disintegrant had been uniformly dispersed within theibuprofen melt. Tablets containing 200 mg ibuprofen were produced. Thedissolution results are given in Table 14 below.

TABLE 14 Dissolution Results at pH 7.2 Time (min) 0  0.0% 5 76.6% 1098.7% 20 99.1% 30 99.1% 45 99.1% 60 99.1%

EXAMPLES 44-45

Ex 44 (% w/w) Ex 45 (% w/w) Granular component: Ibuprofen 79.1 72.2Croscarmellose sodium 11.9 10.8 Tripotassium citrate monohydrate 7.7 —Sodium citrate — 15.7 Sodium lauryl sulphate 0.2 0.2 Extra-granularcomponent: Colloidal silica 0.4 0.4 Stearic acid 0.7 0.7

Examples 44 and 45 were prepared in the same way as described in Example39 except that firstly, the disintegrant was dispersed uniformly withinthe molten ibuprofen; secondly, the diluent (tripotassium citratemonohydrate/sodium citrate) was dispersed uniformly therethrough andfinally the sodium lauryl sulphate was dispersed within the moltenibuprofen. Tablets containing 200 mg ibuprofen were produced. Thedissolution results are given in Table 15 below.

TABLE 15 Dissolution Results Ex 44 Ex 45 TIME (min) pH 7.2 pH 6.0 pH 7.2pH 6.0 0  0.0%  0.0%  0.0%  0.0% 5 49.4% 40.6% 59.8% 47.8% 10 94.7%80.7% 95.2% 85.9% 20 99.5% 93.2% 97.4% 97.6% 30 99.5% 96.2% 97.4% 98.4%45 99.5% 97.2% 97.4% 98.0% 60 99.5% 97.2% 97.4% 97.8%

EXAMPLE 46

(% w/w) Granular Component: Ibuprofen 86.3 Croscarmellose Sodium 12.9Sodium lauryl sulphate 0.2 Extra-granular component: Colloidal Silica0.4 Sodium lauryl sulphate 0.2

Example 46 was prepared in the same way as described in Example 39except that sodium lauryl sulphate was also incorporated in theextra-granular component as well as in the granular component. Tabletscontaining 200 mg ibuprofen were produced.

EXAMPLE 47

(% w/w) Granular Component: Ibuprofen 31.5 Croscarmellose Sodium 4.7Sugar 31.5 Sodium bicarbonate 12.8 Extra-granular component: ColloidalSilica 0.2 Stearic Acid 0.3 Citric Acid Monohydrate 1.6 Sorbitol 15.7Flavouring/Sweeteners 1.7

A dispersible tablet adapted to be dispersed in water prior to ingestionwas prepared in a similar manner to that described in Example1,incorporating sugar and sodium bicarbonate into the melt granule andcitric acid, sorbitol powder, flavourings and sweeteners in the basingingredients. Tablets containing 200 mg ibuprofen were prepared.

EXAMPLE 48

A composition containing the following ingredients was preparedaccording to the processes outlined below:

Ex 48 (% w/w) Granular Composition: Ibuprofen 85.8 Croscarmellose Sodium12.9 Basing ingredients: Colloidal Silica 0.4 Stearic Acid 0.9

EXAMPLE 48a

The ibuprofen was added to a steam-jacketed vessel and heated to 75-80°C. until the ibuprofen was fully molten. The croscarmellose sodium wasadded to the molten ibuprofen and stirred to maintain a suspension ofthe croscarmellose sodium in the molten ibuprofen. The mixture wasdischarged onto a stainless steel tray and allowed to cool. After theentire mass had solidified, it was passed through a cone mill having ascreen with a round hole size of 1 mm. A granulate having a medianparticle size in the range 150-250 μm was collected.

The colloidal silicon dioxide and stearic acid were added to thegranulate and blended until a uniform mixture was formed. The blendedmixture was compressed into tablets on a conventional tabletting machineto form tablets containing 200 mg ibuprofen. Optionally, the tablets maybe coated with a conventional sugar or film coat.

It was found that the tablets produced had the followingcharacteristics:

Tablet Crushing Strength: 30-80 N Tablet Friability: No tablets cappedor broken after 10 minutes Weight loss <0.1%

EXAMPLE 48b

The following Example describes a one step process involving melting,cooling and granulation within the same vessel (as described above) toproduce the melt granulation. The equipment comprises a jacketed vesselwhich allowed steam heating/water cooling, fitted with both a low speedstirrer and a high-speed cutter/granulator. Equipment of this type isavailable from Niro/Fielder Limited. Another example would be of aColette mixer.

The ibuprofen and croscarmellose sodium were added as dry powders to thejacketed vessel. They were heated to 75° C. with stirring until theibuprofen was fully molten and the croscarmellose sodium maintained as asuspension in the liquid ibuprofen. At this stage, the steam heating wasstopped and the vessel cooled by circulating cold water within thejacket. As the mixture cooled, it becomes more viscous. A high speedrotary cutter was set in motion to break down the solidifying mass intoa granulate. The granulate was further milled to produce a granulatehaving a mean particle size of in the range 150-250 μm.

The colloidal silicon dioxide and stearic acid were added to thegranulate and blended until a uniform mixture was formed. The blendedmixture was compressed into tablets containing 200 mg ibuprofen.Optionally, the tablets may be coated with a conventional sugar or filmcoat.

It was found that the tablets produced had the followingcharacteristics:

Tablet Crushing Strength: 30-80 N Tablet Friability: No tablets cappedor broken after 10 minutes Weight loss <0.1%

EXAMPLE 48c

The following Example describes the production of the melt granulationby spray granulation. In this process the ingredients were melted in asuitable vessel and pumped to the spray head of a spray granulator. Themelt was sprayed into the flow of cold air and the resultant granulateformed by the agglomeration of melt onto solidified particles.

The ibuprofen and croscarmellose sodium were added as dry powders to thejacketed vessel. They were heated to 75° C. with stirring until theibuprofen was fully molten and the croscarmellose sodium maintained as asuspension in the liquid ibuprofen.

The mixture was transferred to a spray granulator via a trace-heatedline. The melt dispersion was sprayed into a stream of cold air,controlling the spray rate of feed material and the rate of removal ofthe particles, until suitably sized particles for tabletting wereformed. The granulate was discharged into a container.

The colloidal silicon dioxide and stearic acid were added to thegranulate and blended until a uniform mixture was formed. The blendedmixture was compressed into tablets containing 200 mg ibuprofen.Optionally, the tablets may be coated with a sugar or film coat.

It was found that the tablets produced had the followingcharacteristics:

Tablet Crushing Strength: 30-80 N Tablet Friability: No tablets cappedor broken after 10 minutes Weight loss <0.1%

EXAMPLE 48d

The melt formulation was produced using a spray tower drier. Thisprocess is similar to the spray granulation process but differed in thatthe granulate was formed from a spray dispersion in one step.

The ibuprofen and croscarmellose sodium were added as dry powders to thejacketed vessel. They were heated to 75° C. with stirring until theibuprofen was fully molten and the croscarmellose sodium maintained as asuspension in the liquid ibuprofen.

The mixture was transferred to the spray head, situated at the top of aspray tower via trace-heated line. The melt dispersion was sprayed intoa stream of cold air until particles were formed directly bysolidification of the melt onto solid particles. The cooled solidifiedgranulate was collected and placed in a container.

The colloidal silicon dioxide and stearic acid were added to thegranulate and blended until a uniform mixture was formed. The blendedmixture was compressed into tablets containing 200 mg ibuprofen.Optionally, the tablets may be coated with a conventional sugar or filmcoat.

It was found that the tablets produced had the followingcharacteristics:

Tablet Crushing Strength: 30-80 N Tablet Friability: No tablets cappedor broken after 10 minutes Weight loss <0.1%

EXAMPLE 48e

The ibuprofen and croscarmellose sodium were blended to form a uniformpowder mixture which was then introduced into the heated chamber of atwin screw extruder via a screw-feed hopper system. The extruder barrelwas heated to a temperature given below. The ingredients were heated andworked in the extruder until the ibuprofen was fully molten. Acontinuous molten ribbon of extrudate was discharged onto a cooledstainless steel band to allow the extrudate to cool over a period of upto 1 minute. The solidified mass was broken and passed through a conemill having a screen with a round hole size of 1 mm to produce agranulate having a median particle size in the range 150-250 μm, blendedwith colloidal silicon dioxide and stearic acid until a uniform mixturewas produced. The mixture was compressed to produce tablets containing200 mg ibuprofen. An optional sugar or film coating using conventionalprocess technology may be applied to the tablets.

The following extruders were tried:

Temperature Extruder Model L/D ratio* of barrel Output 1 MP 19   40:117° C.  10 kg/hr 2 MP 19   25:1 80° C.  10 kg/hr 3 MP 19 17.5:1 80° C. 10 kg/hr 4 MP 40PC 17.5:1 90° C. 100 kg/hr *L/D ratio = length:diameter

It was found that the tablets produced had the followingcharacteristics:

Tablet Crushing Strength: 30-80 N Tablet Friability: No tablets cappedor broken after 10 minutes Weight loss < 0.1% Dissolution Results SeeTable 16 below (MP 19 Extruder; L/D ratio 17.5:1)

TABLE 16 Dissolution Results at pH 7.2 Time (min) 0 0.0% 5 82.4% 1096.9% 20 98.9% 30 99.1% 45 99.2% 60 99.2%

In the same way, tablets containing 50 mg, 100 mg, 150 mg, 200 mg, 300mg and 400 mg ibuprofen, S(+)-ibuprofen, flurbiprofen,S(+)-flurbiprofen, ketoprofen, S(+)-ketoprofen, naproxen andS(+)-naproxen can be prepared. Optionally, an inert diluent such as aconventional sugar and/or cellulose material may also be incorporated toaccount for the difference in dosages required to achieve a therapeuticeffect in comparison to the amount of ibuprofen normally incorporatedinto solid dosage forms.

Furthermore, the following disintegrants may replace the disintegrantsillustrated herein in each of the illustrative Examples:

-   wheat starch, maize starch, potato starch, low-substituted    hydroxypropyl cellulose, algnic acid, cross-linked polyvinyl    pyrrolidone and magnesium aluminium silicate.

For example, there may also be prepared the following Examples in asimilar manner to be illustrative Examples previously described:

EXAMPLES 49-55

Ex 49 Ex 50 Ex 51 (% w/w) (% w/w) (% w/w) Granular component: Ibuprofen67.6 65.3 63.3 Croscarmellose Sodium 3.4 6.5 9.5 Extra-granularcomponent: Colloidal Silica 1.0 1.0 1.0 Stearic Acid 0.7 0.7 0.7 SodiumBicarbonate 27.3 26.5 25.5 Ex 55 Ex 52 Ex 53 Ex 54 (% (% w/w) (% w/w) (%w/w) w/w) Granular component: Ibuprofen 82.3  82.3  82.3  82.3 Croscarmellose Sodium 16.3  12.4  12.4  12.2  Sodium Citrate — 4.1 — 4.1Potassium Citrate — — 4.1 — Sodium Lauryl Sulphate 0.2 — — 0.2Extra-granular component: Colloidal Silicon Dioxide 0.4 0.4 0.4 0.4Stearic Acid 0.8 0.8 0.8 0.8 Sodium Lauryl Sulphate — — — —

EXAMPLES 56-61

Ex 56 Ex 57 Ex 58 (% w/w) (% w/w) (% w/w) Granular component: Ibuprofen79.0  79.0  82.3  Croscarmellose Sodium 11.9  11.9  12.2  Sodium Citrate7.9 — — Potassium Citrate — 7.9 4.1 Sodium Lauryl Sulphate — — 0.2Extra-granular component: Colloidal Silicon Dioxide 0.4 0.4 0.8 StearicAcid 0.8 0.8 — Sodium Lauryl Sulphate — — 0.2 Ex 59 Ex 60 Ex 61 (% w/w)(% w/w) (% w/w) Granular component: Ketoprofen (50 mg/tablet) 31.3 45.5  — Naproxen (250 mg/tablet) — — 88.3  Croscarmellose Sodium 5.0 7.210.6  Extra-granular component: Colloidal Silica 0.6 0.9 0.4 StearicAcid 0.6 0.9 0.7 Microcrystalline cellulose 62.5  45.5  —

EXAMPLES 62-64

Ex 62 Ex 63 Ex 64 (% w/w) (% w/w) (% w/w) Granular component: Ibuprofen79.1 79.1 72.2 Croscarmellose sodium 11.9 19.5 11.0 Sodium citrate 7.6 —15.7 Sodium lauryl sulphate 0.2 0.2 — Extra-granular component:Colloidal silicon dioxide 0.4 0.4 0.4 Stearic acid 0.8 0.8 0.7

COMPARATIVE EXAMPLES Comparative Example 1 Compressed Tablets WithoutSilicon Dioxide

The granular component for the comparative Examples was produced in asimilar manner to that described for the illustrative Examples. Thegranular component of comparative Examples A-D contained only meltgranules of ibuprofen together with different amounts of croscarmellosesodium as disintegrating agent. Tablets were formed by compressing thegranular component without any extra-granular component. The granularcomponent of comparative Examples E-H contained ibuprofen andcroscarmellose sodium in different proportions. The granular componentwas combined with 1% stearic acid as the only ingredient in theextra-granular component.

Comparative Example 1

Dissolution time Example 10 mins 20 mins 30 mins 45 mins 60 mins A (5%2.6% 5.7% 9.6% 14.3% 18.8% disintegrating agent) B (8% 2.2% 7.3% 10.1%15.5% 19.9% disintegrating agent) C (10% 0.1% 0.0% −0.1% 0.0% 0.0%disintegrating agent) D (15% −0.9% 3.4% 6.7% 10.8% 15.8% disintegratingagent) E (5% 1.2% 5.5% 8.8% 13.2% 17.9% disintegrating agent) F (8% 0.4%5.8% 8.6% 13.5% 16.6% disintegrating agent) G (10% 2.4% 5.9% 9.7% 15.5%20.4% disintegrating agent) H (15% 1.3% 5.4% 9.8% 14.2% 20.7%disintegrating agent)

It can be seen that the above comparative Example gives relatively poordissolution compared with the illustrative Examples according to thepresent invention.

Comparative Example 2

The following Example is taken from Japanese Patent Application 120616(1981) (Example 5). This example prepares tablets containing 200 mgibuprofen containing the ingredients listed below.

% w/w Ibuprofen 79.4 Microcrystalline cellulose 7.9 Hydroxypropyl starch11.9 Calcium stearate 0.8

The dissolution results at pH 7.2 are provided in Comparative Table 2below.

COMPARATIVE TABLE 2 Dissolution Results at pH 7.2 Time (min) 0 0.0% 513.1% 10 23.4% 20 35.7% 30 43.5% 45 51.8% 60 58.0%

It can be seen that the above comparative Example gives relatively poordissolution compared with the illustrative Examples according to thepresent invention.

Comparative Example 3

The Example 48 formulation was processed through the MP 19 extruder (L/Dratio 17.5:1) in which the barrel was heated to 75° C. (Test A) or 50°C. (Test B). The Ibuprofen in Test A fully melted. However, in Test B, asignificant amount of the Ibuprofen did not melt and thus the ibuprofenwas present as two phases. The dissolution results, at pH 5.8 for Test Aand Test B are given below in Comparative Table 3.

COMPARATIVE TABLE 3 Dissolution Results at pH 5.8 Time (min) Test A TestB 0 0.0% 0.0% 5 41.6% 23.9% 10 66.7% 45.3% 20 85.4% 71.3% 30 92.4% 85.5%45 96.2% 94.0% 60 97.5% 96.6%

It can be seen that the dissolution results for the comparative Example(Test B) are significantly poorer that the dissolution results for acomposition according to present invention (Test A).

The invention claim is:
 1. A compressed tablet composition comprising: agranular component comprising a plurality of solidified melt granules ofa non-steroidal anti-inflammatory drug having a melting point in therange of 30-300° C., wherein a disintegrant is uniformly dispersedtherein; wherein all of the non-steroidal anti-inflammatory drug withinthe granules is present as a single continuous crystalline phase,wherein the tablet composition comprises silicon dioxide present in anamount of 0.05-5.0% by weight of the composition, and wherein thenon-steroidal anti-inflammatory drug is 60-97% by weight of the tabletcomposition.
 2. The compressed tablet composition according to claim 1wherein the silicon dioxide is present as an extra-granular component.3. The compressed tablet composition according to claim 2 wherein theextra-granular component further comprises a lubricant.
 4. Thecompressed tablet composition according to claim 1 wherein the granularcomponent further comprises a surfactant.
 5. The compressed tabletcomposition according to claim 2 wherein a) said granular component is60-99.95% by weight of the composition, and said disintegrant is 0.05-1parts by weight per part by weight of non-steroidal anti-inflammatorydrug; b) said extra-granular component is 0.05-40% by weight of thecomposition.
 6. The compressed tablet composition according to claim 1,wherein the non-steroidal anti-inflammatory drug is selected from thegroup consisting of ibuprofen, flurbiprofen, ketoprofen, naproxen andenantiomers thereof.
 7. The compressed tablet composition according toclaim 1, wherein the non-steroidal anti-inflammatory drug is anibuprofen medicament.
 8. The compressed tablet composition according toclaim 1, wherein the disintegrant is selected from the group consistingof sodium starch glycolate and croscarmellose sodium.
 9. The compressedtablet composition according to claim 1, wherein said silicon dioxide ispresent at 0.1-3% by weight of the composition.
 10. The compressedtablet composition according to claim 1, further comprising diluentwhich is present at 0.1-20% by weight of the composition.
 11. Thecompressed tablet composition according to claim 1, wherein the granularcomponent comprises 70-95% non-steroidal anti-inflammatory drug byweight of the granular component.
 12. The compressed tablet compositionaccording to claim 7, wherein the composition comprises a) 90-99.95%granular component by weight of the composition, said granular componentcomprising solidified melt granules of ibuprofen incorporatingcroscarmellose sodium uniformly dispersed therein, said ibuprofen beingpresent in an amount of 70-99% by weight of the composition, saidcroscarmellose sodium being present in an amount of 1-25% by weight ofthe composition, and further comprising b) 0.05-10% extra-granularcomponent by weight of the composition, wherein said extra-granularcomponent comprises: (i) 0.1-3% lubricant by weight of the composition;and (ii) 0.05-2% silicon dioxide by weight of the composition.
 13. Thecompressed tablet composition according to claim 12, wherein thesolidified melt granules further comprise a diluent uniformly dispersedtherein, and the diluent is present in an amount of up to 20% by weightof the composition.
 14. The compressed tablet composition according toclaim 13, wherein the granular component consists essentially ofibuprofen, croscarmellose sodium and a diluent selected from the groupconsisting of microcrystalline cellulose and a salt of an organic acid.15. The compressed tablet composition according to claim 1, wherein saidnon-steroidal anti-inflammatory drug is ibuprofen in an amount of 70-95%by weight of the composition.
 16. The compressed tablet compositionaccording to claim 1, wherein said disintegrant is croscarmellose sodiumin an amount of 3-20% by weight of the composition.
 17. The compressedtablet composition according to claim 3, wherein said extra-granularcomponent consists essentially of silicon dioxide and a lubricant in aratio of 1 part by weight silicon dioxide to 0.05-5 parts by weightlubricant.
 18. The compressed tablet composition according to claim 10,wherein a) said granular component comprises: (i) 70-90% ibuprofen byweight of the composition; (ii) 8-20% croscarmellose sodium by weight ofthe composition; (iii) 0-20% diluent by weight of the composition; andfurther comprising b) an extra-granular component comprising: (iv)0.5-2% stearic acid or a salt thereof by weight of the composition; (v)0.1-2.5% silicon dioxide by weight of the composition, wherein the sumof components (i) to (v) being greater than 99% by weight of thecomposition.
 19. A method for improving the dissolution of anonsteroidal anti-inflammatory drug from a compressed composition underaqueous conditions, comprising forming a compressed composition bycombining a granular component with an extra-granular silicon dioxidecomponent, said granular component comprising a plurality of solidifiedmelt granules of a non-steroidal anti-inflammatory drug having a meltingpoint in the range of 30-300° C. and incorporating a disintegrantuniformly dispersed therein, wherein said silicon dioxide is present inan amount of 0.05-5% by weight, wherein all of the non-steroidalanti-inflammatory drug within the granules is present as a singlecontinuous crystalline phase, and wherein the non-steroidalanti-inflammatory drug is 60-97% by weight of the composition.
 20. Themethod according to claim 19, wherein the solidified melt granulesfurther comprise a diluent uniformly dispersed therein.
 21. A processfor preparing a compressed tablet composition, comprising: a) combininga non-steroidal anti-inflammatory drug in fully molten form with adisintegrant, to form a uniform mixture; b) cooling said mixture to forma solidified melt; c) forming said solidified melt into granules; d)compressing said granules, to form a compressed tablet composition;wherein the tablet composition comprises a granular component comprisinga plurality of solidified melt granules of a non-steroidalanti-inflammatory drug having a melting point in the range of 30-300°C., wherein a disintegrant is uniformly dispersed therein; wherein thenon-steroidal anti-inflammatory drug within the melt granules is presentas a continuous phase, wherein the tablet composition comprises silicondioxide present in an amount of 0.05 to 5% by weight of the composition,and wherein the non-steroidal anti-inflammatory drug is 60-97% by weightof the tablet composition.
 22. The method according to claim 21, furthercomprising an extra-granular component.
 23. The process according toclaim 21, wherein the silicon dioxide is present as an extra-granularcomponent.
 24. The process according to claim 21, wherein saidnonsteroidal anti-inflammatory drug and said disintegrant are combinedand then heated together until said non-steroidal anti-inflammatory isfully molten.
 25. The process according to claim 21, wherein said drugand said disintegrant are extruded.
 26. The process according to claim25, wherein said drug and said disintegrant are extruded in a twin-screwextruder.
 27. The process according to claim 21, wherein the granulesare combined with an extra-granular component comprising a lubricant andsilicon dioxide prior to compression into tablets.
 28. The processaccording to claim 21, further comprising combining a diluent with thedisintegrant and the drug in fully molten form.
 29. The processaccording to claim 28, further comprising combining a surfactant withsaid diluent and said disintegrant.
 30. A method for treating painand/or inflammation and/or fever comprising administering a compositionaccording to claim 1 to a mammal in need thereof.
 31. A compressedtablet composition comprising: a) a granular component comprising aplurality of solidified melt granules of a non-steroidalanti-inflammatory drug having a melting point in the range of 30-300°C., wherein a disintegrant is uniformly dispersed therein; wherein saidnon-steroidal anti-inflammatory drug is present as a continuous phasewithin the granules obtainable by combining the disintegrant with saidnonsteroidal anti-inflammatory drug wherein said nonsteroidalanti-inflammatory drug is fully molten, wherein the tablet compositionfurther comprises b) silicon dioxide present in an amount of 0.05 to5.0% by weight of the composition, and wherein the non-steroidalanti-inflammatory drug is 60-97% by weight of the tablet composition.32. The compressed tablet composition according to claim 31 wherein thesilicon dioxide is present as an extra-granular component.
 33. Thecompressed tablet composition according to claim 32 wherein theextra-granular component further comprises a lubricant.
 34. Thecompressed tablet composition according to claim 31 wherein the granularcomponent further comprises a surfactant.
 35. The compressed tabletcomposition according to claim 32 wherein a) said granular component is60-99.95% by weight of the composition, and said disintegrant is 0.05-1parts by weight per part by weight of nonsteroidal anti-inflammatorydrug; and b) said extra-granular component is 0.05-40% by weight of thecomposition.
 36. The compressed tablet composition according to claim31, wherein the non-steroidal anti-inflammatory drug is selected fromthe group consisting of ibuprofen, flurbiprofen, ketoprofen, naproxenand enantiomers thereof.
 37. The compressed tablet composition accordingto claim 31, wherein the non-steroidal anti-inflammatory drug is anibuprofen medicament.
 38. The compressed tablet composition according toclaim 31, wherein the disintegrant is selected from the group consistingof sodium starch glycolate and croscarmellose sodium.
 39. The compressedtablet composition according to claim 31, wherein said silicon dioxideis present at 0.1-3% by weight of the composition.
 40. The compressedtablet composition according to claim 31, further comprising diluentwhich is present at 0.1-20% by weight of the composition.
 41. Thecompressed tablet composition according to claim 31, wherein thegranular component comprises 70-95% non-steroidal anti-inflammatory drugby weight of the granular component.
 42. The compressed tabletcomposition according to claim 37, wherein the composition comprises a)90-99.95% granular component by weight of the composition, said granularcomponent comprising solidified melt granules of ibuprofen incorporatingcroscarmellose sodium uniformly dispersed therein, said ibuprofen beingpresent in an amount of 70-99% by weight of the composition, saidcroscarmellose sodium being present in an amount of 1-25% by weight ofthe composition, and further comprising b) 0.05-10% extra-granularcomponent by weight of the composition, wherein said extra-granularcomponent comprises: (i) 0.1-3% lubricant by weight of the composition;and (ii) 0.05-2% silicon dioxide by weight of the composition.
 43. Thecompressed tablet composition according to claim 42, wherein thesolidified melt granules further comprise a diluent uniformly dispersedtherein, and the diluent is present in an amount of up to 20% by weightof the composition.
 44. The compressed tablet composition according toclaim 43, wherein the granular component consists essentially ofibuprofen, croscarmellose sodium and a diluent selected from the groupconsisting of microcrystalline cellulose and a salt of an organic acid.45. The compressed tablet composition according to claim 31, whereinsaid non-steroidal anti-inflammatory drug is ibuprofen in an amount of70-95% by weight of the composition.
 46. The compressed tabletcomposition according to claim 31, wherein said disintegrant iscroscarmellose sodium in an amount of 3-20% by weight of thecomposition.
 47. The compressed tablet composition according to claim33, wherein said extra-granular component consists essentially ofsilicon dioxide and a lubricant in a ratio of 1 part by weight silicondioxide to 0.05-5 parts by weight lubricant.
 48. The compressed tabletcomposition according to claim 40, wherein said granular componentcomprises: (i) 70-90% ibuprofen by weight of the composition; (ii) 8-20%croscarmellose sodium by weight of the composition; and (iii) 0-20%diluent by weight of the composition; and further comprising anextra-granular component comprising: (iv) 0.5-2% stearic acid or a saltthereof by weight of the composition; and (v) 0.1-2.5% silicon dioxideby weight of the composition, wherein the sum of components (i) to (v)being greater than 99% by weight of the composition.
 49. A compressedtablet composition comprising: a granular component comprising aplurality of solidified melt granules of a non-steroidalanti-inflammatory drug having a melting point in the range of 30-300°C., wherein a disintegrant is uniformly dispersed therein; wherein allof the non-steroidal anti-inflammatory drug within the granules ispresent as a single continuous phase, the tablet composition comprisessilicon dioxide present in an amount of 0.05-5.0% by weight of thecomposition, the silicon dioxide is present as an extra-granularcomponent, and wherein the non-steroidal anti-inflammatory drug is60-97% by weight of the tablet composition.
 50. A compressed tabletcomposition comprising: a) a granular component comprising a pluralityof solidified melt granules of a non-steroidal anti-inflammatory drughaving a melting point in the range of 30-300° C., wherein adisintegrant is uniformly dispersed therein; wherein said non-steroidalanti-inflammatory drug is present as a continuous phase within thegranules obtainable by combining the disintegrant with said nonsteroidalanti-inflammatory drug wherein said nonsteroidal anti-inflammatory drugis fully molten, wherein the tablet composition further comprises b) anextra-granular component comprising silicon dioxide present in an amountof 0.05 to 5.0% by weight of the composition, wherein the non-steroidalanti-inflammatory drug is 60-97% by weight of the tablet composition.51. The compressed tablet composition according to claim 1, wherein saiddisintegrant is uniformly dispersed into said non-steroidalanti-inflammatory drug while said non-steroidal anti-inflammatory drugis in molten form.
 52. The compressed tablet composition according toclaim 1, further comprising a salt of an organic acid.
 53. Thecompressed tablet composition according to claim 52, wherein the salt ofan organic acid is sodium citrate.